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Science: AIDS drug goes on trial in manipulated mice

By
ROGER LEWIN in
WASHINGTON DC

DRUGS FOR AIDS can now be tested in mice with a human immune system.
The mice, known as SCID-hu mice – for ‘severe combined immune deficiency
human tissue’ – were developed more than a year ago by genetic engineers
in California (‘A mouse with a human immune system’, New Scientist, 14 January
1989). Now, researchers are using them as living laboratories in which to
study how AIDS affects the human immune system and to test drugs against
the disease.

The development is important because HIV is very choosy about which
organisms it will infect. Only chimpanzees provide a reasonable animal model
for the human disease, and they are rare and expensive. The lack of a laboratory
model for the human immune system up until now has been a tremendous hindrance
to AIDS researchers.

Joseph McCune, of SyStemix, a biotechnology company in California, set
out to ‘build’ a mouse that could be infected with HIV. Mice normally shrug
off the virus. To create this more vulnerable mouse, McCune, who was formerly
at Stanford University, took a strain of mice that is genetically devoid
of any immune defences. He developed a way of implanting various elements
of the human immune system into them – tissue from the thymus, lymph node,
fetal liver, and so on.

To test the new immune system, McCune and his colleagues chose a very
simple experiment: they implanted 1 cubic millimetre of intact tissue from
the human thymus just under the skin of each SCID-hu mouse. They then injected
a dose of HIV directly into the thymus implant, to see if an infection could
be established in the human tissue. They found that all of the 40 animals
they tested were indeed infected.

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The next step was to inject a dose of HIV into the mice after treating
them with zidovudine, formerly known as AZT, the only drug that is licensed
for the treatment of AIDS in humans. The team at SyStemix found that zidovudine
suppressed the production of viruses in all 17 of the animals they tested.
They also found that when treatment with zidovudine is stopped, viral production
takes off. This is precisely what happens in humans (Science, vol 247, p
564).

The aim of McCune and his colleagues was to establish a system that
was better than today’s most economical method of screening potential drugs
against HIV. The method involves culturing certain human immune cells in
a test tube, particularly T cells.

McCune and his colleagues were able to achieve their aim with the SCID-hu
mice, because thymus tissue produces T cells. Furthermore, the immune system
of SCID-hu mice is more realistic physiologically for HIV infection than
the cell culture. This is because the implant is a piece of intact thymus
tissue.

The challenge facing the team at SyStemix is to repeat the experiments,
this time with tissue from the human lymph node. This is much more tricky
to work with. But it is potentially more important, because such tissue
generates a greater range of immune cells than thymus tissue can, including
B cells which produce antibodies. A SCID-hu mouse implanted with human lymph
node would, therefore, be a better model of the human body.

So far, the SyStemix team has established SCID-hu mice with implants
of lymph node. Their experiments on HIV infection are still in progress.
They are particularly interested in seeing whether the mice produce antibodies
against HIV, because the production of antibodies is a natural component
of the human response to infection with HIV.

SCID-hu mice cannot be a complete model for the spread of HIV in humans
because only the human cells in the animals’ bodies become infected with
the virus. But the mice seem likely to offer the promise of insights into
some aspects of the disease – and at a price researchers can afford. At
the very least, they provide a means by which potential AIDS drugs can be
screened for antiviral effect, before they are taken to the next step.